Abuse of amphetamines is a major public health problem that warrants the identification of genetic risk factors which could lead to addiction prevention and novel treatments. Because amphetamines are also used clinically for such conditions as Attention Deficit Hyperactive Disorder, Parkinson's disease, and narcolepsy, studying the genetic basis of the biological actions of these drugs could also lead to improved pharmaceutical treatments. This application requests support for training in mouse and human genetics to test the hypothesis that polymorphisms in the candidate gene casein kinase 1-epsilon (Csnk1-e) contribute to sensitivity to the behavioral and subjective effects of amphetamines in mice and humans. In Aim 1, mice will be bred with polymorphic Csnk1-e alleles on two separate isogenic background strains with the hypothesis that Csnk1-e polymorphisms will modulate the locomotor stimulant response to methamphetamine (MA). In Aim 2, polymorphism-induced changes in Csnkle gene expression will be examined along with changes in MA-induced activation of the Darpp-32 dopamine signaling pathway and MA-induced locomotor activity in mice. The hypothesis is that an increase in Csnkle expression will result in an increase in MA-induced Darpp-32 phosphorylation and an increase in the locomotor stimulant response to MA. Furthermore, we expect these changes in Csnkle expression to result in differential sensitivity to the biochemical and behavioral effects of specific pharmacological inhibition of Csnkle. In Aim 3, parallel to the mouse studies, a human translational study will be conducted whereby association of CSNK1E polymorphisms with sensitivity to the physiological, behavioral, and subjective responses to d- amphetamine (AMPH) will be examined, including AMPH euphoria. Public Health Relevance: New insight into the genetic basis for sensitivity to amphetamines may have important implications for addiction prevention as well as the development of novel treatments for clinical conditions related to dysregulation of the dopamine system.